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Wirth M.,TU Munich | Stojanovic N.,TU Munich | Christian J.,McGill University | Paul M.C.,TU Munich | And 6 more authors.
Nucleic Acids Research | Year: 2014

The c-MYC (MYC afterward) oncogene is well known for driving numerous oncogenic programs. However, MYC can also induce apoptosis and this function of MYC warrants further clarification. We report here that a clinically relevant proteasome inhibitor significantly increases MYC protein levels and that endogenous MYC is necessary for the induction of apoptosis. This kind of MYC-induced cell death is mediated by enhanced expression of the pro-apoptotic BCL2 family members NOXA and BIM. Quantitative promoter-scanning chromatin immunoprecipitations (qChIP) further revealed binding of MYC to the promoters of NOXA and BIM upon proteasome inhibition, correlating with increased transcription. Both promoters are further characterized by the presence of tri-methylated lysine 4 of histone H3, marking active chromatin.We provide evidence that in our apoptosis models cell death occurs independently of p53 or ARF. Furthermore, we demonstrate that recruitment of MYC to the NOXA as well as to the BIM gene promoters depends on MYC's interaction with the zinc finger transcription factor EGR1 and an EGR1-binding site in both promoters. Our study uncovers a novel molecular mechanism by showing that the functional cooperation of MYC with EGR1 is required for bortezomib-induced cell death. This observation may be important for novel therapeutic strategies engaging the inherent pro-death function of MYC. © 2014 The Author(s).


Gebauer J.S.,University of Duisburg - Essen | Malissek M.,University of Duisburg - Essen | Simon S.,Friedrich - Alexander - University, Erlangen - Nuremberg | Knauer S.K.,University of Duisburg - Essen | And 5 more authors.
Langmuir | Year: 2012

In biological fluids, proteins may associate with nanoparticles (NPs), leading to the formation of a so-called "protein corona" largely defining the biological identity of the particle. Here, we present a novel approach to assess apparent binding affinities for the adsorption/desorption of proteins to silver NPs based on the impact of the corona formation on the agglomeration kinetics of the colloid. Affinities derived from circular dichroism measurements complement these results, simultaneously elucidating structural changes in the adsorbed protein. Employing human serum albumin as a model, apparent affinities in the nanomolar regime resulted from both approaches. Collectively, our findings now allow discrimination between the formation of protein mono- and multilayers on NP surfaces. © 2012 American Chemical Society.


Klug F.,German Cancer Research Center | Prakash H.,German Cancer Research Center | Prakash H.,University of Heidelberg | Prakash H.,University of Hyderabad | And 17 more authors.
Cancer Cell | Year: 2013

Inefficient Tcell migration is a major limitation of cancer immunotherapy. Targeted activation of the tumor microenvironment may overcome this barrier. We demonstrate that neoadjuvant local low-dose gamma irradiation (LDI) causes normalization of aberrant vasculature and efficient recruitment of tumor-specific Tcells in human pancreatic carcinomas and T-cell-mediated tumor rejection and prolonged survival in otherwise immune refractory spontaneous and xenotransplant mouse tumor models. LDI (local or pre-adoptive-transfer) programs the differentiation of iNOS+ M1 macrophages that orchestrate CTL recruitment into and killing within solid tumors through iNOS by inducing endothelial activation and the expression of TH1 chemokines and by suppressing the production of angiogenic, immunosuppressive, and tumor growth factors. © 2013 Elsevier Inc.


Bier C.,University Hospital of Mainz | Knauer S.K.,University of Duisburg - Essen | Docter D.,University Hospital of Mainz | Schneider G.,TU Munich | And 2 more authors.
Traffic | Year: 2011

Taspase1 is a threonine protease suspected to process (patho)biologically relevant nuclear and cytoplasmic substrates, such as the mixed lineage leukemia protein. However, neither the mechanisms regulating Taspase1's intracellular localization nor their functional consequences are known. Analysis of endogenous and ectopically expressed Taspase1 detected the protease predominantly in the nucleus accumulating at the nucleolus. Microinjection and ectopic expression studies identified an evolutionarily conserved bipartite nuclear import signal (NLS) (amino acids 197KRNKRKLELA ERVDTDFMQLKKRR220) interacting with importin-α. Notably, an NLS-mutated, import-deficient Taspase1 was biologically inactive. Although the NLS conferred nuclear transport already of the proenzyme, Taspase1's nucleolar localization required its autoproteolytic processing, triggering its interaction with the nucleolar shuttle protein nucleophosmin. In contrast, (auto)catalytically inactive Taspase1 mutants neither accumulated at the nucleolus nor bound nucleophosmin. Active nuclear import and interaction with nucleophosmin was found to be required for the formation of proteolytically active Taspase1 ensuring to efficiently process its nuclear targets. Intriguingly, coexpression of pathological nucleophosmin variants increased the amount of cytoplasmic Taspase1. Hence, Taspase1 appears to exploit the nuclear export activity of nucleophosmin to gain transient access to the cytoplasm required to also cleave its cytoplasmic substrates. Collectively, we here describe a hitherto unknown mechanism regulating the biological activity of this protease. © 2011 John Wiley & Sons A/S.


Pless B.,Goethe University Frankfurt | Oehm C.,Goethe University Frankfurt | Knauer S.,University of Duisburg - Essen | Stauber R.H.,University Hospital of Mainz | And 2 more authors.
Leukemia | Year: 2011

The chromosomal translocation t(4;11)(q21;q23) is a frequent genetic aberration of the mixed lineage leukemia (MLL) gene, predominantly associated with high-risk acute lymphoblastic leukemia (ALL) in pediatric patients. Previous studies demonstrated that mice transplanted with hematopoietic cells expressing the AF4-MLL fusion protein develop proB ALL. The AF4-MLL oncoprotein becomes activated by Taspase1-mediated hydrolysis, which subsequently leads to a heterodimer of the cleavage products AF4-MLLN and MLLC. This protein-protein interaction is due to the FYRN and FYRC interaction domains present in both protein fragments. Heterodimerization subsequently induces high-molecular-weight protein complex formation that is protected against SIAH1/2-mediated polyubiquitinylation. Here, we attempted to selectively block this initial heterodimerization step, aiming to prevent the oncogenic activation of the AF4-MLL multiprotein complex. The minimal interaction interface was experimentally defined first in a bacterial two-hybrid system, and then in mammalian cells by using a biosensor assay. Expression of the FYRC domain, or smaller portions thereof, resulted in the inhibition of heterodimer formation, and blocked AF4-MLL multiprotein complex formation with subsequent destruction of the AF4-MLL oncoprotein. Thus, it is in principle possible to specifically target the AF4-MLL protein. This knowledge can now be exploited to design inhibitory decoys in order to destroy the AF4-MLL oncoprotein. © 2011 Macmillan Publishers Limited All rights reserved.


Noelken R.,University of Mainz | Kunkel M.,University Hospital of Bochum | Wagner W.,University Hospital of Mainz
Clinical Oral Implants Research | Year: 2014

Background: Placement of implants into extraction sockets targets the maintenance of peri-implant hard and soft tissue structures and the support of a natural and esthetic contour. The main advantages of immediate implant insertion in comparison with delayed implant placement protocols are as follows: a reduced treatment time, less number of sessions, and, thus, the less invasive procedure. This study examines the clinical performance (survival rate, marginal bone levels and Pink Esthetic Score [PES]) of OsseoSpeed™ implants placed into extraction sockets with immediate provisionalization in the anterior maxilla after a follow-up of at least 12 months. Methods: Twenty patients received a total number of 37 OsseoSpeed™ implants which were immediately inserted into extraction sockets with or without facial bone deficiencies of various dimensions. A flapless procedure was applied, and the implants were immediately provisionalized with temporary crowns without occlusal contacts. Facial gaps between implant surface and facial bone or the previous contour of the alveolar process were grafted with autogenous bone chips. Implants in diameters 3.5, 4.0, 4.5, and 5.0 with lengths of 11-17 mm were used in the study. During the course of the study, interproximal marginal bone levels, the thickness of the facial bony wall, implant success rate according to the criteria established by Buser, and the PES were assessed per implant. Results: One patient with three implants did not continue the study after prosthesis delivery, the remaining 34 implants were still in function at the final follow-up (survival rate: 100%). The mean follow-up period was 27 months (range, 12-40 months). Marginal bone height at the level of the implant shoulder averaged -0.1 ± 0.55 mm (range, -1.25 to 1.47 mm) at the final follow-up. The mean PES ratings were 11.3 ± 1.8 (range, 6-14) at the final follow-up. In 78% of the patients, the PES was preserved or even improved. Conclusions: Success rates, marginal bone levels, and esthetic results suggest proof of principle for the preservation of marginal bone height at immediately placed and provisionalized OsseoSpeed™ implants after a follow-up of at least 12 months. Even implant sites with facial bony deficiencies can be successfully treated with a favorable esthetic outcome using the immediate implant insertion, immediate reconstruction, and immediate provisionalization technique. © 2013 John Wiley & Sons A/S.


Heinrich S.,University Hospital of Mainz | Lang H.,University Hospital of Mainz
Journal of Surgical Oncology | Year: 2013

Liver resection has become standard for the treatment of metastatic colorectal cancer (CRC): anterior approach, hanging manoeuvre, or total vascular exclusion techniques as well as 3-dimensional imaging enable safe resections even in difficult cases. Furthermore, modern chemotherapy, portal vein embolization/ligation, and two-stage procedures increase the resectability of metastasis, and repeat resections are feasible for recurrence. In addition to characteristics of the primary, CEA, extent of metastasis, resection margins, and extrahepatic disease, hilar lymph node metastases appear prognostic. © 2012 Wiley Periodicals, Inc.


Gori T.,University Hospital of Mainz | Fineschi M.,University of Siena
Cardiovascular Therapeutics | Year: 2012

We set out to describe the clinical characteristics of patients presenting with acute or stable coronary syndromes and no stenosis in epicardial coronaries. Although the existence of patients who experience typical angina and who have intact epicardial coronaries is well accepted, the pathophysiology of cardiac ischemia in this setting remains poorly understood. In typical coronary syndrome X, it is believed that at least two components play a role: the first is the incapacity of coronary resistance vessels to adapt to situations of increased blood demand, resulting in demand ischemia; the second is an inappropriate transduction or generation or pain stimuli within the central nervous system. These two mechanisms concur to determine episodes of precordial pain and electrocardiogram (ECG) evidence of ischemia during exercise. In contrast, the coronary slow-flow phenomenon, or syndrome Y, is an angiographic finding that is characterized by delayed progression of the contrast medium during coronary angiography. Although the mechanism of this phenomenon remains largely unknown, it has been proposed that it might depend on the presence of inappropriately high resting coronary resistances, causing reduced blood flow and therefore low-flow ischemia and unstable angina. Importantly, the prognosis of many of the patients presenting with coronary slow-flow does not appear to be favorable, with recurrence of acute coronary syndromes and life-threatening arrhythmias. In the present article, we revise the current evidence regarding these two phenomena, and propose that syndrome Y should be considered a separate clinical entity. © 2010 Blackwell Publishing Ltd.


Battistelli S.,University of Siena | Genovese A.,University of Siena | Gori T.,University Hospital of Mainz
American Journal of Surgery | Year: 2010

Background: Unfractionated and low-molecular-weight heparin are commonly used in the prevention and therapy of a variety of cardiovascular diseases. Because the major side effects of these drugs are hemorrhagic events, very little attention is paid to another important side effect (ie, heparin-induced thrombocytopenia [HIT]). HIT is an immune-mediated transient prothrombotic state with very severe implications determined by thromboembolic phenomena in both the venous and arterial circulation. Data sources: A PubMed search from 1995 to 2008 was performed. Pertinent literature was identified and other references retrieved from bibliographic citations of the articles identified on PubMed. Articles related to the pathogenesis, clinical picture, diagnosis and treatment of HIT were reviewed. Conclusions: HIT is a potentially fatal but treatable and largely preventable disease. An increased awareness of the signs and symptoms of the disorder is necessary to prevent its potentially devastating complications. © 2010.


Hempel J.-M.,University Hospital of Mainz | Greif-Higer G.,University Hospital of Mainz | Kaufmann T.,University Hospital of Mainz | Beutel M.E.,University Hospital of Mainz
Liver Transplantation | Year: 2012

Alcoholic liver cirrhosis (ALC) is a commonly accepted indication for liver transplantation (LT). Any alcohol consumption is considered a contraindication for LT. However, the assessment of abstinence in everyday practice mostly relies on patient self-reporting, which must be considered highly unreliable. After consumption, ethanol is eliminated by alcohol dehydrogenase, with methanol accumulating in the blood. Methanol, which is known to be a sensitive and specific indicator for recent alcohol consumption, has not been used for verifying alcohol consumption in LT assessments yet. Therefore, the purpose of this study was to test the feasibility of using methanol testing to identify recent alcohol consumption in LT candidates during routine and short-notice appointments. We compared methanol and ethanol measurements with self-reported alcohol consumption for 41 patients with ALC during the evaluation process before they were accepted onto the waiting list. In 32 of the 92 blood samples drawn from these 41 patients during the study, a relapse was detected by the methanol test. Both the ethanol test results and the self-reported data were positive in only 3 cases. Thus, the methanol test identified 29 additional cases of alcohol consumption. Furthermore, the methanol test discovered recent alcohol consumption in 5 of 10 transplant patients when both self-reported data and ethanol test results were negative. As a part of blood alcohol analysis, the methanol test is more sensitive than self-reporting and ethanol testing for the detection of recent alcohol consumption. Also, short-notice appointments for blood alcohol analysis reveal more cases of alcohol relapse than routine, long-term appointments. The measurement of methanol as a sensitive screening test for recent alcohol consumption should be implemented both in law and in daily, routine practice. © 2012 AASLD.

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